Papovaviruses are DNA viruses with very small genomes; yet they are both transforming and tumorigenic. The human Papilloma viruses are well-established malignant tumor-generating agents in man. Polyoma virus is a murine carcinogen, and recent evidence suggests that an SV40-like agent triggers the development of an aggressive human skin cancer. These viruses each encode a very small number of proteins, of which only a fraction act to elicit a neoplastic phenotype and to sustain tumor development. Through their analysis, major insights into widely encountered molecular events that trigger and maintain a neoplastic state have emerged. In this Program renewal application, an interactive research plan aimed at gaining ever deeper mechanistic understanding of papovaviral transformation and tumorigenesis is proposed. Six projects will, collectively, investigate major mysteries in the field: how cells escape and how they reenter the cell cycle, both naturally and when stimulated by papovaviral T antigens; why and how two related papovaviral small T antigens can act as an oncogene and as a potential tumor suppressor, respectively; how papovaviral small T perturbation of the protein phosphatase, PP2A, triggers powerful transforming signals through corruption of specific cellular signal transduction events; why and how SV40 large T antigen engages a mitotic checkpoint kinase as a key event in its transforming action; and how a papilloma virus regulatory protein (E2) operates as a tumor suppressing element. The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies.